Stable crystalline apalutamide in pure form, and process for the preparation thereof

Abstract

The present invention relates to a novel non-solvated crystalline form of apalutamide in pure, stable form, and the process for the preparation thereof.

1 . Apalutamide crystalline form Y, having the following characteristics:
 i. an x-ray diffraction spectrum (XRPD) as reported in  FIG. 1  including peaks at 7.8°±0.2°2θ, 10.3°±0.2°2θ, 12.3°±0.2°2θ, 15.3°±0.2°2θ, 18.7°±0.2°2θ and 22.5°±0.2°2θ (Cu-K-alpha 1° λ=1.54060);   ii. an IR spectrum as reported in  FIG. 2 ;   iii. a DSC profile with a thermal gradient ranging from 40.0° C. to 220° C. at 10.0° C./minute as reported in  FIG. 3 ;   iv. an acetonitrile content lower than 410 ppm.   
     
     
         2 . A process for the preparation of apalutamide form Y of  claim 1  which comprises crystallizing crude apalutamide from acetonitrile or a mixture of acetonitrile and an acetonitrile-miscible solvent, followed by drying at 30-90° C. in the presence of water for a time of 3-18 h. 
     
     
         3 . The process according to  claim 2  wherein the acetonitrile-miscible solvent is selected from water, methanol, acetone, tetrahydrofuran, toluene, cyclohexane, dimethyl carbonate, cyclopentyl methyl ether, dimethylsulphoxide and dichloromethane. 
     
     
         4 . The process according to  claim 2  wherein the apalutamide-solvent ratio ranges from 1:1 to 1:30. 
     
     
         5 . The process according to  claim 2  wherein crystallisation is carried out by cooling at a temperature ranging from 0 to 25° C., or by addition of an anti-solvent selected from water, toluene and cyclopentyl methyl ether. 
     
     
         6 . The process according to  claim 2  wherein drying is carried out at 55-70° C. with humidity ranging from 20 to 50% in 5-100. 
     
     
         7 . Apalutamide crystalline acetonitrile solvated form, which has the following characteristics:
 i. an x-ray diffraction spectrum (XRPD) including peaks at 7.7°±0.2°2θ, 10.4°±0.2°2θ, 12.3°±0.2°2θ, 15.4°±0.2°2θ, 17.9°±0.2°2θ and 22.4°±0.2°2θ (Cu—K-alpha 1° λ=1.54060) as reported in  FIG. 4 ;   ii. an IR spectrum as reported in  FIG. 5 ;   iii. a DSC profile with a thermal gradient ranging from 40.0° C. to 220° C. at 10.0° C./minute as reported in  FIG. 6 ;   iv. an oxo-apalutamide content of less than 0.05%.   
     
     
         8 . The process according to  claim 4 , wherein the apalutamide-solvent ratio ranges from 1:5. 
     
     
         9 . The process according to  claim 5 , wherein crystallization is carried out by cooling at a temperature ranging from 10 to 20° C. 
     
     
         10 . The process according to  claim 5 , wherein the crystallization is carried out by addition of water. 
     
     
         11 . The process according to  claim 6 , wherein drying is carried out with humidity ranging at 40%. 
     
     
         12 . The process according to  claim 6 , wherein drying is carried out in 48 hours.